Evaluation of the transcriptional factor HNF4± in beta cell function, viability and differentiation state, in conditions that can lead to development of Diabetes Mellitus

• Grant number: 19/26062-9
• Support Opportunities: Regular Research Grants
• Start date: June 01, 2020
• End date: May 31, 2022
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Fernanda Ortis
• Grantee: Fernanda Ortis
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Gustavo Jorge dos Santos ; Sandra Mara Ferreira

Abstract

Diabetes Mellitus (DM) is characterized by chronic hyperglycemia that can compromise life quality and span. Since preservation of beta-cell functional mass is a central point for prevention of DM it is of extreme importance a better understanding of the mechanisms involved in this dysfunction. In the past few year our group have being studding the transcription factor HNF4alpha in beta-cells and its involvement with beta-cell ER stress viability and function. The role of HNF4ap in beta-cell have being showed by the description of a rare type of DM, the Maturity Onset Diabetes of the Young (MODY) 1, caused by mutations on HNF4alpha gene codifying region. Data from our group showed that HNF4alpha seems to be important for maintenance of beta-cell differentiate state, which maybe related with incapability to respond to metabolic demand with beta-cell increase in cells that lack HNF4alpha. In addition, we showed beta-cell silenced for HNF4alpha are resistant to pro-inflammatory cytokines-induced cell death, via modulation of ER stress markers. Thus, we intend in this project to evaluate the molecular pathways involved in HNF4alpha modulation by pro-inflammatory cytokines in beta-cell and its "crosstalk" with ER stress, NF-kB activation and miRNA expression. We also intent to evaluate if the latency for MODY1 symptoms to appear in humans could be related to increase beta-cell phenotype during maturity or with incapability of beta-cells lacking HNF4alpha to maintain ER homeostasis, as observed in vitro, using an animal model. A better understanding of HNF4alpha influence in conditions that can lead to DM development has a great potential for development of therapies for preservation of beta-cell or even cure for DM. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

VILAS-BOAS, ELOISA APARECIDA; ALMEIDA, DAVIDSON CORREA; ROMA, LETICIA PRATES; ORTIS, FERNANDA; CARPINELLI, ANGELO RAFAEL. Lipotoxicity and beta-Cell Failure in Type 2 Diabetes: Oxidative Stress Linked to NADPH Oxidase and ER Stress. CELLS, v. 10, n. 12, DEC 2021. (17/26339-5, 17/04580-2, 19/26062-9, 14/50867-3, 20/06184-0)

PIMENTEL VILLACA, CATHARINA DE BARROS; DE PAULA, CAROLINA CAVALCANTE; DE OLIVEIRA, CAROLINE CRUZ; VILAS-BOAS, ELOISA APARECIDA; DOS SANTOS-SILVA, JUNIA CAROLINA; DE OLIVEIRA, SERGIO FERREIRA; ABDULKADER, FERNANDO; FERREIRA, SANDRA MARA; ORTIS, FERNANDA. Beneficial effects of physical exercise for beta-cell maintenance in a type 1 diabetes mellitus animal model. Experimental Physiology, v. 106, n. 7, p. 1482-1497, JUL 2021. (14/50867-3, 17/04580-2, 19/26062-9)